Tissue repair involves the cellular behaviors and molecular effectors of embryonic morphogenesis, and resembles the host response to invading cancers and metastases. Despite its precise orchestration, tissue repair is often incomplete or chronic, commonly due to infection. Many molecules involved in repair bind to heparin/heparan sulfate. The syndecan family of transmembrane proteoglycans is the major source of cell surface heparan sulfate, and serves as receptors or co-receptors for a variety of ligands. The syndecan extracellular domains (ectodomains) are shed from cell surfaces via receptor activation by agents involved in wound repair; shedding instantly changes syndecan function from cell surface receptor or co-receptor to soluble effector. Syndecan expression is highly regulated during skin wound repair. Syndecan-1 is lost from migratory keratinocytes, but induced in dermal capillaries, syndecan-4 is induced in dermal fibroblasts, and syndecan-1 and - ectodomains are shed into wound fluid where they regulate growth factor and proteolytic balance. Syndecan-1 null and syndecan-1 over- expression mice both show impaired skin wound repair, but by distinct mechanisms. These data lead to an overall hypothesis that syndecans coordinate, in part, the reparative response to tissue injury. Study of this hitherto unrecognized role provides new approaches to pathogenesis that should uncover novel preventive and/or therapeutic interventions.